Arylethanolamine beta2-adrenoreceptor agonist compounds

ABSTRACT

The present invention relates to compounds of formula (I) as defined herein and salts or solvates thereof. Processes for preparing these compounds and pharmaceutical formulations containing them are also disclosed, as well as methods for the prophylaxis of treatment of a clinical condition using such compounds.

The present invention is concerned with phenethanolamine derivatives,processes for their preparation, compositions containing them and theiruse in medicine, particularly in the prophylaxis and treatment ofrespiratory diseases.

Certain phenethanolamine compounds are known in the art as havingselective stimulant action at β₂-adrenoreceptors and therefore havingutility in the treatment of bronchial asthma and related disorders. ThusGB 2 140 800 describes phenethanolamine compounds including4-hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol1-hydroxy-2-naphthalenecarboxylate (salmeterol xinafoate) which is nowused clinically in the treatment of such medical conditions.

Although salmeterol and the other commercially availableβ₂-adrenoreceptor agonists are effective bronchodilators, the maximumduration of action is 12 hours, hence twice daily dosing is oftenrequired. There is therefore a clinical need for compounds having potentand selective stimulant action at β₂-adrenoreceptors and having anadvantageous profile of action.

According to the present invention, there is provided a compound offormula (I)

or a salt, solvate, or physiologically functional derivative thereof,wherein:

n is an integer of from 2 to 8;

m is an integer of from 3 to 11, preferably from 3 to 7, with theproviso that the sum of n+m is from 5 to 19, preferably 5 to 12;

R¹ is hydrogen or —XSO₂NR⁶R⁷;

wherein X is —(CH₂)_(p)— or C₂₋₆ alkenylene;

p is an integer from 0 to 6, preferably 0 to 4;

R⁶ and R⁷ are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, CONR⁸R⁹, phenyl and phenyl(C₁₋₄alkyl)-,

or R⁶ and R⁷, together with the nitrogen atom to which they are bonded,form a 5-, 6- or 7-membered nitrogen—containing ring;

and R⁶ and R⁷ are each independently optionally substituted by 1 or 2groups independently selected from halo, C₁₋₆alkyl, C₁₋₆alkoxy,hydroxy-substituted C₁₋₆alkoxy, C₁₋₆haloalkyl, CO₂R⁸, SO₂R⁸R⁹, —CONR⁸R⁹,—NR⁸C(O)R⁹ or a 5-, 6- or 7-membered heterocyclic ring;

R⁸ and R⁹ are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl and phenyl(C₁₋₆alkyl)-;

R² and R³ are independently selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy, halo, phenyl and C₁₋₆haloalkyl;

R⁴ and R⁵ are independently selected from hydrogen and C₁₋₄ alkyl withthe proviso that the total number of carbon atoms in R⁴ and R⁵ is notmore than 4, and

Ar is a group selected from

wherein R¹¹ represents hydrogen, halogen, —(CH₂)_(q)OR¹⁴, —NR¹⁴C(O)R¹⁵,—NR¹⁴SO₂R¹⁵, —SO₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —OC(O)R¹⁶ or OC(O)NR¹⁴R¹⁵,

and R¹⁰ represents hydrogen, halogen or C₁₋₄alkyl;

or R¹¹ represents —NHR¹⁷ and R¹⁰ and —NHR¹⁷ together form a 5- or6-membered heterocyclic ring;

R¹² represents hydrogen, halogen, —OR¹⁴ or —NR¹⁴R¹⁵;

R¹³ represents hydrogen, halogen, haloC₁₋₄alkyl, —OR¹⁴, —NR¹⁴R¹⁵OC(O)R¹⁶or OC(O)NR¹⁴R¹⁵;

R¹⁴ and R¹⁵ each independently represents hydrogen or C₁₋₄ alkyl, or inthe groups —NR¹⁴R¹⁵, —SO₂NR¹⁴R¹⁵ and —OC(O)NR¹⁴R¹⁵, R¹⁴ and R¹⁵independently represent hydrogen or C₁₋₄ alkyl or together with thenitrogen atom to which they are attached form a 5-, 6- or 7-memberednitrogen-containing ring,

R¹⁶ represents an aryl (eg phenyl or naphthyl) group which may beunsubstituted or substituted by one or more substituents selected fromhalogen, C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy or halo C₁₋₄ alkyl; and

q is zero or an integer from 1 to 4;

provided that when R¹ is hydrogen

Ar is not a group (a) wherein;

R¹¹ is —(CH₂)_(q)OR¹⁴, q is zero or 1 and R¹² is OR¹⁴,

or R¹¹ is —(CH₂)_(q)OR¹⁴, q is zero and R¹³ is OR¹⁴,

or R¹¹ is —NR¹⁴SO₂R¹⁵ or NR¹⁴COR¹⁵ and R¹² is OR¹⁴,

or R¹¹ and R¹³ both represent halogen and R¹² is NR¹⁴R¹⁵;

Ar is not a group (b) wherein R¹¹ is —(CH₂)_(q)OR¹⁴ and R¹² is OR¹⁴;

Ar is not a group (c),

and when R¹ is XSO₂NR⁶R⁷, Ar is not a group (a) wherein

R¹¹ is (CH₂)_(q)OR¹⁴ or NR¹⁴COR¹⁵, and R¹² is OR¹⁴.

In a particular embodiment of this invention, in the group Ar, R¹¹represents halogen, —(CH₂)_(q)OR¹⁴, —NR¹⁴C(O)R¹⁵, —NR¹⁴SO₂R¹⁵,—SO₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —OC(O)R¹⁶ or OC(O)NR¹⁴R¹⁵,

and R¹⁰ represents hydrogen,

or R¹¹ represents —NHR¹⁷ and R¹⁰ and —NHR¹⁷ together form a 5- or6-membered heterocyclic ring; and

R¹³ represents hydrogen, halogen, haloC₁₋₄ alkyl, —OR¹⁴, or —NR¹⁴R¹⁵;

and all other substituents are as defined above.

In the compounds of formula (I), the group R¹ is preferably attached tothe meta-position relative to the —O—(CH₂)_(m) link.

R¹ preferably represents SO₂NR⁶R⁷ wherein R⁶ and R⁷ are independentlyselected from hydrogen and C₁₋₆alkyl. More preferably R¹ is SO₂NH₂.

R⁴ and R⁵ are preferably independently selected from hydrogen andmethyl, more preferably R⁴ and R⁵ are both hydrogen.

In the compounds of formula (I) R² and R³ preferably each representhydrogen.

The integer n is suitably 4, 5 or 6 and m is suitably 3, 4, 5 or 6.Preferably n is 5 or 6 and m is 3 or 4 such that m+n is 8, 9 or 10,preferably 9.

In the compounds of formula (I) the group Ar is preferably selected fromgroups (a) and (b) above. In said groups (a) and (b), when R¹¹represents halogen this is preferably chlorine or fluorine, especiallyfluorine. R¹⁴ and R¹⁵ preferably each independently represent hydrogenor methyl. R¹⁶ preferably represents substituted phenyl. The integer qpreferably represents zero or 1. Thus for example —(CH₂)_(q)OR¹⁴preferably represents OH or —CH₂OH;

NR¹⁴C(O)R¹⁵ preferably represents —NHC(O)H;

—SO₂NR¹⁴R¹⁵ preferably represents —SO₂NH₂ or SO₂NHCH₃;

NR¹⁴R¹⁵ preferably represents —NH₂;

—OC(O)R¹⁶ preferably represents substituted benzoyloxy eg.OC(O)—C₆H₄—(_(p)—CH₃); and

—OC(O)NR¹⁴R¹⁵ preferably represents OC(O)N(CH₃)₂.

When R¹¹ represents NHR¹⁷ and together with R¹⁰ forms a 5- or 6-memberedheterocyclic ring —NHR¹⁷—R¹⁰— preferably represents a group:

—NH—CO—R¹⁸ where R¹⁸ is an alkylene, and alkenylene or alkenyloxy group,

—NH—SO₂R¹⁹ where R¹⁹ is an alkenyloxy group,

—NH—R²⁰ (COOR²¹) where R¹⁹ is an alkylene or alkenylene group and R²⁰ isC₁₋₄ alkyl, or

—NH—CO—CH— or NH—CO—S,

wherein said alkylene, and alkenylene groups and moieties contain 1 or 2carbon atoms.

Particularly preferred groups (a) and (b) may be selected from thefollowing groups (i) to (xx):

wherein the dotted line in (xv) and (xviii) denotes an optional doublebond.

It will be appreciated that when R¹ represents hydrogen, Ar is not agroup having the structure (i), (iii), (iv), (vii) or (x). Furthermore,when R¹ represents a group —XSO₂NR⁶R⁷, Ar is not a group having thestructure (ii).

Thus, when R¹ is hydrogen, Ar is preferably selected from a group ofstructure (ii), (v), (vi), (viii), (ix), (xi), (xii), (xiii), (xiv),(xv), (xvi), (xvii) and (xviii).

Most preferably when R¹ is hydrogen Ar is selected from a group ofstructure (xiv), (xv), (xvi) and (xvii).

When R¹ is XSO₂NR⁶R⁷, Ar is preferably selected from a group ofstructure (iii), (iv), (xiv), (xv), (xvi) and (xix).

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.

Preferred compounds of the invention include:

8-Hydroxy-5-((1R)-1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)quinolin-2(1H)-one;

3-{4-[(6-{[(2R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;

5-Hydroxy-8-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-2H-1,4-benzoxazin-3(4H)-one;

3-{4-[(6-{[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;

4-Hydroxy-7-((1R)-1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-1,3-benzothiazol-2(3H)-one;

4-Hydroxy-7-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-1,3-benzothiazol-2(3H)-one;

3-{4-[(6-{[(2R)-2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;

3-(4-{[6-({2-Hydroxy-2-[5-hydroxy-6-(hydroxymethyl)pyridin-2-yl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;

3-[4-({6-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]hexyl}oxy)butyl]benzenesulfonamide;

3-{3-[(7-{[(2R)-2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]amino}heptyl)oxy]propyl}benzenesulfonamide;

3-(3-{[7-({2-Hydroxy-2-[5-hydroxy-6-(hydroxymethyl)pyridin-2-yl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide;

3-[3-({7-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]heptyl}oxy)propyl]benzenesulfonamide;

3-{3-[(7-{[(2R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}heptyl)oxy]propyl}benzenesulfonamide;

3-(3-{[7-({(2R)-2-[3-(Formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)heptyl]oxy}propyl)benzenesulfonamide;

and salts, solvates and physiologically functional derivatives thereof.

The compounds of formula (I) include an asymmetric centre, namely thecarbon atom of the

group. The present invention includes both (S) and (R) enantiomerseither in substantially pure form or admixed in any proportions.Preferably, the compounds of the invention are in the form of the (R)enantiomers.

Similarly, where R⁴ and R⁵ are different groups, the carbon atom towhich they are attached is an asymmetric centre and the presentinvention includes both (S) and (R) enantiomers at this centre either insubstantially pure form or admixed in any proportions.

Thus the compounds of formula (I) include all enantiomers anddiastereoisomers as well as mixtures thereof in any proportions.

Salts and solvates of compounds of formula (I) which are suitable foruse in medicine are those wherein the counterion or associated solventis pharmaceutically acceptable.

However, salts and solvates having non-pharmaceutically acceptablecounterions or associated solvents are within the scope of the presentinvention, for example, for use as intermediates in the preparation ofother compounds of formula (I) and their pharmaceutically acceptablesalts, solvates, and physiologically functional derivatives.

By the term “physiologically functional derivative” is meant a chemicalderivative of a compound of formula (I) having the same physiologicalfunction as the free compound of formula (I), for example, by beingconvertible in the body thereto. According to the present invention,examples of physiologically functional derivatives include esters.

Suitable salts according to the invention include those formed with bothorganic and inorganic acids or bases. Pharmaceutically acceptable acidaddition salts include those formed from hydrochloric, hydrobromic,sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic,trifluoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic,oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic,methanesulphonic, ethanesulphonic, arylsulphonic (for examplep-toluenesulphonic, benzenesulphonic, naphthalenesulphonic ornaphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic,cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy orhalo substituted cinnamic, including 4-methyl and 4-methoxycinnamicacid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or3-hydroxy-2-naphthoic), naphthaleneacrylic (for examplenaphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (forexample 1,4-benzenediacrylic) and isethionic acids. Pharmaceuticallyacceptable base salts include ammonium salts, alkali metal salts such asthose of sodium and potassium, alkaline earth metal salts such as thoseof calcium and magnesium and salts with organic bases such asdicyclohexyl amine and N-methyl-D-glucamine.

Pharmaceutically acceptable esters of the compounds of formula (I) mayhave a hydroxyl group converted to a C₁₋₆alkyl, aryl, aryl C₁₋₆ alkyl,or amino acid ester.

As mentioned above, the compounds of formula (I) are selectiveβ₂-adrenoreceptor agonists as demonstrated using functional or reportergene readout from cell lines transfected with human beta-adrenoreceptorsas described below. Compounds according to the present invention alsohave the potential to combine long duration of effect with rapid onsetof action. Furthermore, certain compounds have shown an improvedtherapeutic index in animal models relative to existing long-actingβ₂-agonist bronchodilators. As such, compounds of the invention may besuitable for once-daily administration.

Therefore, compounds of formula (I) and their pharmaceuticallyacceptable salts, solvates, and physiologically functional derivativeshave use in the prophylaxis and treatment of clinical conditions forwhich a selective β₂-adrenoreceptor agonist is indicated. Suchconditions include diseases associated with reversible airwaysobstruction such as asthma, chronic obstructive pulmonary diseases(COPD) (e.g. chronic and wheezy bronchitis, emphysema), respiratorytract infection and upper respiratory tract disease.

Other conditions which may be treated include premature labour,depression, congestive heart failure, skin diseases (e.g. inflammatory,allergic, psoriatic, and proliferative skin diseases), conditions wherelowering peptic acidity is desirable (e.g. peptic and gastriculceration) and muscle wasting disease.

Accordingly, the present invention provides a method for the prophylaxisor treatment of a clinical condition in a mammal, such as a human, forwhich a selective β₂-adrenoreceptor agonist is indicated, whichcomprises administration of a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt, solvate,or physiologically functional derivative thereof. In particular, thepresent invention provides such a method for the prophylaxis ortreatment of a disease associated with reversible airways obstructionsuch as asthma, chronic obstructive pulmonary disease (COPD),respiratory tract infection or upper respiratory tract disease. In afurther aspect the present invention provides such a method for theprophylaxis or treatment of a clinical condition selected from prematurelabour, depression, congestive heart failure, skin diseases (e.g.inflammatory, allergic, psoriatic, and proliferative skin diseases),conditions where lowering peptic acidity is desirable (e.g. peptic andgastric ulceration) or muscle wasting disease.

In the alternative, there is also provided a compound of formula (I), ora pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof for use in medical therapy, particularly,for use in the prophylaxis or treatment of a clinical condition in amammal, such as a human, for which a selective β₂-adrenoreceptor agonistis indicated.

In particular, there is provided a compound of formula (I), or apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof for the prophylaxis or treatment of a diseaseassociated with reversible airways obstruction such as asthma, chronicobstructive pulmonary disease (COPD), respiratory tract infection orupper respiratory tract disease. In a further aspect, there is provideda compound of formula (I), or a pharmaceutically acceptable salt,solvate, or physiologically functional derivative thereof for theprophylaxis or treatment of a clinical condition selected from prematurelabour, depression, congestive heart failure, skin diseases (e.g.inflammatory, allergic, psoriatic, and proliferative skin diseases),conditions where lowering peptic acidity is desirable (e.g. peptic andgastric ulceration) or muscle wasting disease.

The present invention also provides the use of a compound of formula(I), or a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof in the manufacture of a medicament for theprophylaxis or treatment of a clinical condition for which a selectiveβ₂-adrenoreceptor agonist is indicated, for example a disease associatedwith reversible airways obstruction such as asthma, chronic obstructivepulmonary disease (COPD), respiratory tract infection or upperrespiratory tract disease. In a further aspect, there is provided acompound of formula (I), or a pharmaceutically acceptable salt, solvate,or physiologically functional derivative thereof in the manufacture of amedicament for the prophylaxis or treatment of a clinical conditionselected from premature labour, depression, congestive heart failure,skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferativeskin diseases), conditions where lowering peptic acidity is desirable(e.g. peptic and gastric ulceration) and muscle wasting disease.

The amount of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof which is required to achieve a therapeutic effect will, ofcourse, vary with the particular compound, the route of administration,the subject under treatment, and the particular disorder or diseasebeing treated. The compounds of the invention may be administered byinhalation at a dose of from 0.0005 mg to 10 mg, preferably 0.005 mg to0.5 mg. The dose range for adult humans is generally from 0.0005 mg to100 mg per day and preferably 0.01 mg to 1 mg per day.

While it is possible for the compound of formula (I), or apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof to be administered alone, it is preferable to presentit as a pharmaceutical formulation.

Accordingly, the present invention further provides a pharmaceuticalformulation comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof, and a pharmaceutically acceptable carrier or excipient, andoptionally one or more other therapeutic ingredients.

Hereinafter, the term “active ingredient” means a compound of formula(I), or a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), inhalation (including fine particle dusts or mistswhich may be generated by means of various types of metered dosepressurised aerosols, nebulisers or insufflators), rectal and topical(including dermal, buccal, sublingual and intraocular) administrationalthough the most suitable route may depend upon for example thecondition and disorder of the recipient. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing the active ingredient into association with thecarrier which constitutes one or more accessory ingredients. In generalthe formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition ofthe sterile liquid carrier, for example saline or water-for-injection,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of for examplegelatine, or blisters of for example laminated aluminium foil, for usein an inhaler or insufflator. Formulations generally contain a powdermix for inhalation of the compound of the invention and a suitablepowder base (carrier substance) such as lactose or starch. Use oflactose is preferred. Each capsule or cartridge may generally containbetween 20 μg-10 mg of the compound of formula (I) optionally incombination with another therapeutically active ingredient.Alternatively, the compound of the invention may be presented withoutexcipients. Packaging of the formulation may be suitable for unit doseor multi-dose delivery. In the case of multi-dose delivery, theformulation can be pre-metered (eg as in Diskus, see GB 2242134 orDiskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (eg asin Turbuhaler, see EP 69715). An example of a unit-dose device isRotahaler (see GB 2064336). The Diskus inhalation device comprises anelongate strip formed from a base sheet having a plurality of recessesspaced along its length and a lid sheet hermetically but peelably sealedthereto to define a plurality of containers, each container havingtherein an inhalable formulation containing a compound of formula (I)preferably combined with lactose. Preferably, the strip is sufficientlyflexible to be wound into a roll. The lid sheet and base sheet willpreferably have leading end portions which are not sealed to one anotherand at least one of the said leading end portions is constructed to beattached to a winding means. Also, preferably the hermetic seal betweenthe base and lid sheets extends over their whole width. The lid sheetmay preferably be peeled from the base sheet in a longitudinal directionfrom a first end of the said base sheet.

Spray compositions for topical delivery to the lung by inhalation mayfor example be formulated as aqueous solutions or suspensions or asaerosols delivered from pressurised packs, such as a metered doseinhaler, with the use of a suitable liquefied propellant. Aerosolcompositions suitable for inhalation can be either a suspension or asolution and generally contain the compound of formula (I) optionally incombination with another therapeutically active ingredient and asuitable propellant such as a fluorocarbon or hydrogen-containingchlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes,e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxideor other suitable gas may also be used as propellant. The aerosolcomposition may be excipient free or may optionally contain additionalformulation excipients well known in the art such as surfactants egoleic add or lecithin and cosolvents eg ethanol. Pressurisedformulations will generally be retained in a canister (eg an aluminiumcanister) closed with a valve (eg a metering valve) and fitted into anactuator provided with a mouthpiece.

Medicaments for administration by inhalation desirably have a controlledparticle size. The optimum particle size for inhalation into thebronchial system is usually 1-10 μm, preferably 2-5 μm. Particles havinga size above 20 μm are generally too large when inhaled to reach thesmall airways. To achieve these particle sizes the particles of theactive ingredient as produced may be size reduced by conventional meanseg by micronisation. The desired fraction may be separated out by airclassification or sieving. Preferably, the particles will becrystalline. When an excipient such as lactose is employed, generally,the particle size of the excipient will be much greater than the inhaledmedicament within the present invention. When the excipient is lactoseit will typically be present as milled lactose, wherein not more than85% of lactose particles will have a MMD of 60-90 μm and not less than15% will have a MMD of less than 15 μm.

Intranasal sprays may be formulated with aqueous or non-aqueous vehicleswith the addition of agents such as thickening agents, buffer salts oracid or alkali to adjust the pH, isotonicity adjusting agents oranti-oxidants.

Solutions for inhalation by nebulation may be formulated with an aqueousvehicle with the addition of agents such as acid or alkali, buffersalts, isotonicity adjusting agents or antimicrobials. They may besterilised by filtration or heating in an autoclave, or presented as anon-sterile product.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured basis such as sucrose and acacia ortragacanth, and pastilles comprising the active ingredient in a basissuch as gelatin and glycerin or sucrose and acacia.

Preferred unit dosage formulations are those containing an effectivedose, as hereinbefore recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavouring agents.

The compounds and pharmaceutical formulations according to the inventionmay be used in combination with or include one or more other therapeuticagents, for example selected from anti-inflammatory agents,anticholinergic agents (particularly an M₁, M₂, M₁/M₂ or M₃ receptorantagonist), other β₂-adrenoreceptor agonists, antiinfective agents(e.g. antibiotics, antivirals), or antihistamines. The invention thusprovides, in a further aspect, a combination comprising a compound offormula (I) or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof together with one or moreother therapeutically active agents, for example selected from ananti-inflammatory agent (for example a corticosteroid or an NSAID), ananticholinergic agent, another β₂-adrenoreceptor agonist, anantiinfective agent (e.g. an antibiotic or an antiviral), or anantihistamine. Preferred are combinations comprising a compound offormula (I) or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof together with acorticosteroid, and/or an anticholinergic, and/or a PDE-4 inhibitor.Preferred combinations are those comprising one or two other therapeuticagents.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredient(s) may be used in the form of salts,(e.g. as alkali metal or amine salts or as acid addition salts), orprodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g.hydrates) to optimise the activity and/or stability and/or physicalcharacteristics (e.g. solubility) of the therapeutic ingredient. It willbe clear also that where appropriate, the therapeutic ingredients may beused in optically pure form.

Suitable anti-inflammatory agents include corticosteroids and NSAIDs.Suitable corticosteroids which may be used in combination with thecompounds of the invention are those oral and inhaled corticosteroidsand their pro-drugs which have anti-inflammatory activity. Examplesinclude methyl prednisolone, prednisolone, dexamethasone, fluticasonepropionate,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11α-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-35-yl) ester, beclomethasone esters (e.g.the 17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (e.g. the furoate ester), triamcinoloneacetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541,and ST-126. Preferred corticosteroids include fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester and6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, more preferably6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitorsor mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors ofleukotriene synthesis, iNOS inhibitors, tryptase and elastaseinhibitors, beta-2 integrin antagonists and adenosine receptor agonistsor antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g.chemokine antagonists) or inhibitors of cytokine synthesis. Suitableother β₂-adrenoreceptor agonists include salmeterol (e.g. as thexinafoate), salbutamol (e.g. as the sulphate or the free base),formoterol (e.g. as the fumarate), fenoterol or terbutaline and saltsthereof.

Of particular interest is use of the compound of formula (I) incombination with a phosphodiesterase 4 (PDE4) inhibitor or a mixedPDE3/PDE4 inhibitor. The PDE4-specific inhibitor useful in this aspectof the invention may be any compound that is known to inhibit the PDE4enzyme or which is discovered to act as a PDE4 inhibitor, and which areonly PDE4 inhibitors, not compounds which inhibit other members of thePDE family as well as PDE4. Generally it is preferred to use a PDE4inhibitor which has an IC₅₀ ratio of about 0.1 or greater as regards theIC₅₀ for the PDE4 catalytic form which binds rolipram with a highaffinity divided by the IC₅₀ for the form which binds rolipram with alow affinity. For the purposes of this disclosure, the cAMP catalyticsite which binds R and S rolipram with a low affinity is denominated the“low affinity” binding site (LPDE 4) and the other form of thiscatalytic site which binds rolipram with a high affinity is denominatedthe “high affinity” binding site (HPDE 4). This term “HPDE4” should notbe confused with the term “hPDE4” which is used to denote human PDE4.

A method for determining IC₅₀ ratios is set out in U.S. Pat. No.5,998,428, which is incorporated herein in full by reference as thoughset out herein. See also PCT application WO 00/57599 for anotherdescription of said assay.

The preferred PDE4 inhibitors of use in this invention will be thosecompounds which have a salutary therapeutic ratio, i.e., compounds whichpreferentially inhibit CAMP catalytic activity where the enzyme is inthe form that binds rolipram with a low affinity, thereby reducing theside effects which apparently are linked to inhibiting the form whichbinds rolipram with a high affinity. Another way to state this is thatthe preferred compounds will have an IC₅₀ ratio of about 0.1 or greateras regards the IC₅₀ for the PDE4 catalytic form which binds rolipramwith a high affinity divided by the IC₅₀ for the form which bindsrolipram with a low affinity.

A further refinement of this standard is that of one wherein the PDE4inhibitor has an IC₅₀ ratio of about 0.1 or greater; said ratio is theratio of the IC₅₀ value for competing with the binding of 1 nM of[³H]R-rolipram to a form of PDE4 which binds rolipram with a highaffinity over the IC₅₀ value for inhibiting the PDE4 catalytic activityof a form which binds rolipram with a low affinity using 1 μM[³H]-cAMPas the substrate.

Most preferred are those PDE4 inhibitors which have an IC₅₀ ratio ofgreater than 0.5, and particularly those compounds having a ratio ofgreater than 1.0. Preferred compounds are cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];these are examples of compounds which bind preferentially to the lowaffinity binding site and which have an IC₅₀ ratio of 0.1 or greater.

Other Compounds of Interest Include:

Compounds set out in U.S. Pat. No. 5,552,438 issued 03 Sep. 1996; thispatent and the compounds it discloses are incorporated herein in full byreference. The compound of particular interest, which is disclosed inU.S. Pat. No. 5,552,438, iscis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomalast) and its salts, esters, pro-drugs orphysical forms;

AWD-12-281 from elbion (Hofgen, N. et al. 15th EFMC Int Symp Med Chem(September 6-10, Edinburgh) 1998, Abst P. 98; CAS reference No.247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM);D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; abenzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34from Kyowa Hakko; V-11294A from Napp (Landells, L. J. et al. Eur Resp J[Annu Cong Eur Resp Soc (September 19-23, Geneva) 1998] 1998, 12 (Suppl.28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and apthalazinone (WO99/47505, the disclosure of which is hereby incorporatedby reference) from Byk-Gulden; Pumafentrine,(−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284(1): 162), andT2585.

Other possible PDE-4 and mixed PDE3/PDE4 inhibitors include those listedin WO01/13953, the disclosure of which is hereby incorporated byreference.

Suitable anticholinergic agents are those compounds that act asantagonists at the muscarinic receptor, in particular those compoundswhich are antagonists of the M₁ and M₂ receptors. Exemplary compoundsinclude the alkaloids of the belladonna plants as illustrated by thelikes of atropine, scopolamine, homatropine, hyoscyamine; thesecompounds are normally administered as a salt, being tertiary amines.These drugs, particularly the salt forms, are readily available from anumber of commercial sources or can be made or prepared from literaturedata via, to wit:

Atropine—CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropinesulfate—CAS-5908-99-6; atropine oxide—CAS4438-22-6 or its HClsalt—CAS-4574-60-1 and methylatropine nitrate—CAS-52-88-0.

Homatropine—CAS-87-00-3, hydrobromide salt—CAS-51-56-9, methylbromidesalt—CAS-80-49-9.

Hyoscyamine (d, l)—CAS-101-31-5, hydrobromide salt—CAS-306-03-6 andsulfate salt—CAS-6835-16-1.

Scopolamine—CAS-51-34-3, hydrobromide salt—CAS-6533-68-2, methylbromidesalt—CAS-155-41-9.

Preferred anticholinergics include ipratropium (e.g. as the bromide),sold under the name Atrovent, oxitropium (e.g. as the bromide) andtiotropium (e.g. as the bromide) (CAS-139404-48-1). Also of interestare: methantheline (CAS-53-46-3), propantheline bromide (CAS-50-34-9),anisotropine methyl bromide or Valpin 50 (CAS-80-50-2), clidiniumbromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamideiodide (CAS-71-81-8), mepenzolate bromide (U.S. Pat. No. 2,918,408),tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocycliummethylsulfate (Tral, CAS-115-63-9). See also cyclopentolatehydrochloride (CAS-5870-29-1), tropicamide (CAS-1508-75-4),trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine(CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116, ormethoctramine, and the compounds disclosed in WO01/04118, the disclosureof which is hereby incorporated by reference.

Suitable antihistamines (also referred to as H₁-receptor antagonists)include any one or more of the numerous antagonists known which inhibitH₁-receptors, and are safe for human use. All are reversible,competitive inhibitors of the interaction of histamine withH₁-receptors. The majority of these inhibitors, mostly first generationantagonists, have a core structure, which can be represented by thefollowing formula:

This generalized structure represents three types of antihistaminesgenerally available: ethanolamines, ethylenediamines, and alkylamines.In addition, other first generation antihistamines include those whichcan be characterized as based on piperizine and phenothiazines. Secondgeneration antagonists, which are non-sedating, have a similarstructure-activity relationship in that they retain the core ethylenegroup (the alkylamines) or mimic the tertiary amine group withpiperizine or piperidine. Exemplary antagonists are as follows:

Ethanolamines: carbinoxamine maleate, clemastine fumarate,diphenylhydramine hydrochloride, and dimenhydrinate.

Ethylenediamines: pyrilamine amleate, tripelennamine HCl, andtripelennamine citrate.

Alkylamines: chlropheniramine and its salts such as the maleate salt,and acrivastine.

Piperazines: hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl,cyclizine lactate, meclizine HCl, and cetirizine HCl.

Piperidines: Astemizole, levocabastine HCl, loratadine or itsdescarboethoxy analogue, and terfenadine and fexofenadine hydrochlorideor another pharmaceutically acceptable salt.

Azelastine hydrochloride is yet another H₁ receptor antagonist which maybe used in combination with a PDE4 inhibitor.

Examples of preferred anti-histamines include methapyrilene andloratadine.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together with aPDE4 inhibitor.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together with acorticosteroid.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together withan anticholinergic.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together withan antihistamine.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together with aPDE4 inhibitor and a corticosteroid.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together withan anticholinergic and a PDE-4 inhibitor.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with aphysiologically acceptable diluent or carrier represent a further aspectof the invention.

The individual compounds of such combinations may be administered eithersequentially or simultaneously in separate or combined pharmaceuticalformulations. Appropriate doses of known therapeutic agents will bereadily appreciated by those skilled in the art.

According to a further aspect of the invention, there is provided aprocess for preparing a compound of formula (I), or a salt, solvate, orphysiologically functional derivative thereof which comprises a process(a), (b), (c) or (d) as defined below followed by the following steps inany order

-   -   (i) optional removal of any protecting groups;    -   (ii) optional separation of an enantiomer from a mixture of        enantiomers;    -   (iii) optional conversion of the product to a corresponding        salt, solvate,    -   (iv) optional conversion of a group R¹, R² and/or R³ to another        group R¹, R² and/or R³,        or physiologically functional derivative thereof.

In the following description of synthetic routes, R¹, R², R³, R⁴, R⁵, mand n are as defined for formula (I) and R²⁵, R²⁶, and R²⁷ are asdefined for formula (II) below unless indicated otherwise.

In one general process (a), a compound of formula (I), may be obtainedby deprotection of a protected intermediate, for example of formula(II):

or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, m and n are asdefined for the compounds of formula (I), and R²⁵ represents anoptionally protected form of Ar and R²⁶ and R²⁷ each independentlyrepresents either hydrogen or a protecting group, provided that thecompound of formula (II) contains at least one protecting group.

Protected forms of the preferred groups Ar may be selected from:

wherein R²⁸ and R²⁹ are each independently either hydrogen or aprotecting group provided that at least one of R²⁸ and R²⁹ is aprotecting group; and the dotted line in (xviiia) and (xxa) denotes anoptional double bond.

Suitable protecting groups may be any conventional protecting group suchas those described in “Protective Groups in Organic Synthesis” byTheodora W Greene and Peter G M Wuts, 3rd edition (John Wiley & Sons,1999). Examples of suitable hydroxyl protecting groups represented byR²⁸ and R²⁹ are esters such as acetate ester, aralkyl groups such asbenzyl, diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl.Examples of suitable amino protecting groups represented by R²⁶ includebenzyl, α-methylbenzyl, diphenylmethyl, triphenylmethyl,benzyloxycarbonyl, tert-butoxycarbonyl, and acyl groups such astrichloroacetyl or trifluoroacetyl.

As will be appreciated by the person skilled in the art, use of suchprotecting groups may include orthogonal protection of groups in thecompounds of formula (II) to facilitate the selective removal of onegroup in the presence of another, thus enabling selectivefunctionalisation of a single amino or hydroxyl function. For example,the —CH(OH) group may be orthogonally protected as —CH(OR²⁷) using, forexample, a trialkylsilyl group such as triethylsilyl. A person skilledin the art will also appreciate other orthogonal protection strategies,available by conventional means as described in Theodora W Greene andPeter G M Wuts (see above).

The deprotection to yield a compound of formula (I), may be effectedusing conventional techniques. Thus, for example, when R²⁸, R²⁹, and/orR²⁶ is an aralkyl group, this may be cleaved by hydrogenolysis in thepresence of a metal catalyst (e.g. palladium on charcoal).

When R²⁸ and/or R²⁹ is tetrahydropyranyl this may be cleaved byhydrolysis under acidic conditions. Acyl groups represented by R²⁶ maybe removed by hydrolysis, for example with a base such as sodiumhydroxide, or a group such as trichloroethoxycarbonyl may be removed byreduction with, for example, zinc and acetic acid. Other deprotectionmethods may be found in Theodora W Greene and Peter G M Wuts (seeabove).

In a particular embodiment of process (a), when R²⁵ represents a group(iiia) R²⁸ and R²⁹ may together represent a protecting group as in thecompound of formula (III):

or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R²⁶, R²⁷, mand n are as defined for the compound of formula (II), and R³⁰ and R³¹are independently selected from hydrogen, C₁₋₆alkyl, or aryl or R³⁰ andR³¹ together form a carbocyclic ring eg. containing from 5 to 7 carbonatoms.

The compound of formula (III) may be converted to a compound of formula(I), by hydrolysis with dilute aqueous acid, for example acetic acid orhydrochloric acid in a suitable solvent or by transketalisation in analcohol, for example ethanol, in the presence of a catalyst such as anacid (for example, toluenesulphonic acid) or a salt (such as pyridiniumtosylate) at normal or elevated temperature.

It will be appreciated that the protecting groups R²⁸, R²⁹, R²⁶ and R²⁷(including the cyclised protecting group formed by R³⁰ and R³¹ asdepicted in formula (III) may be removed in a single step orsequentially. The precise order in which protecting groups are removedwill in part depend upon the nature of said groups and will be readilyapparent to the skilled worker. Preferably, when R³⁰ and R³¹ togetherform a protecting group as in formula (III) this protecting group isremoved together with any protecting group on the CH(OH) moiety,followed by removal of R²⁶.

Compounds of formulae (II) and (III) wherein R²⁶ is hydrogen may beprepared from the corresponding compound of formula (IV).

or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R²⁵, m and nare as defined for the compound of formula (II) or (III).

The conversion of a compound of formula (IV) to a compound of formula(II) or (III) may be effected by treatment with a base, for example anon-aqueous base, such as potassium trimethylsilanolate, or an aqueousbase such as aqueous sodium hydroxide, in a suitable solvent such astetrahydrofuran.

Compounds of formula (IV) may be prepared by reacting a compound offormula (V):

with a compound of formula (VI):

Wherein L is a leaving group such as halo (typically chloro, bromo oriodo) or a sulphonate (typically methanesulphonate) and R¹, R², R³, R⁴,R⁵, n and m are as defined for compounds of formula (I).

The coupling of a compound of formula (V) with a compound of formula(VI) may be effected in the presence of a base, such as a metal hydride,for example sodium hydride, or an inorganic base such as cesiumcarbonate, in an aprotic solvent, for example N,N-dimethylformamide.

Compounds of formula (V) may be prepared by ring closure of a compoundof formula (VII):

wherein R²⁵ is as hereinbefore defined and R³³ is C₁₋₆alkyl, for exampletert-butyl, or aryl, for example phenyl. The ring closure may beeffected by treatment with a base, such as a metal hydride, for examplesodium hydride, in the presence of an aprotic solvent, for example,N,N-dimethylformamide.

The compound of formula (VII) may be prepared from the correspondinghalide of formula (VIII):

wherein R²⁵ and Y are as hereinbefore defined, by reaction with aprotected amine HN(COOR³³)₂, wherein R³³ is as defined for the compoundof formula (VII), in the presence of an inorganic base such as cesiumcarbonate, followed by selective removal of one of the COOR³³ groups,for example by treatment with an acid such as trifluoroacetic acid, andsubsequent reduction of the keto function by any suitable method, forexample by treatment with borane, in the presence of a chiral catalyst,such as CBS-oxazaborolidine, in a suitable solvent such astetrahydrofuran.

A compound of formula (VI) may be prepared by coupling a compound offormula (IX):LCR⁴R⁵(CH₂)_(n)O(CH₂)_(m-2)C≡CH   (IX)wherein L is a leaving group as defined for formula (VI);

with a compound of formula (X):

Wherein L¹ is a leaving group as hereinbefore defined for L and R¹, R²,R³, are as hereinbefore defined, followed by reduction.

The coupling of a compound of formula (IX) with a compound of formula(X) is conveniently effected in the presence of a catalyst system suchas bis(triphenyphosphine)palladium dichloride with an organic base suchas a trialkylamine, for example diisopropylethylamine, in a suitablesolvent for example acetonitrile or dimethylformamide or using the baseas solvent. The resulting alkyne may then be reduced, either with orwithout being isolated to form the desired saturated alcohol. Thereduction may be effected by any suitable method such a hydrogenation inthe presence of a catalyst, for example palladium/charcoal or platinumoxide.

Compounds of formula (X) are commercially available or may be preparedby methods well known to the person skilled in the art.

A compound of formula (IX) may be prepared by reacting a compound offormula (XI):HO(CH₂)_(m-2)C≡CH   (XI)

Wherein m is as defined for formula (I) with a dihaloalkane of formula(XII):Y¹CR⁴R⁵(CH₂)_(n)Y²   (XII)wherein R⁴, R⁵ and n are as hereinbefore defined and Y¹ and Y² eachrepresent halo.

The reaction of compounds (XI) and (XII) is typically effected in thepresence of an inorganic base, such as sodium hydroxide under phasetransfer conditions in the presence of a tetra-alkylammonium salt, eg.tetrabutylammonium bromide.

Compounds of formulae (XI) and (XII) are available commercially or canbe prepared by standard methods.

Alternatively, compounds of formula (II) and (III) wherein R²⁶ is eitherhydrogen or a protecting group may be prepared by any of the processesdescribed hereinafter.

In a further process (b) a compound of formula (I) may be obtained byreacting a compound of formula (XIII):

Wherein Ar is as defined above, with a compound of formula (VI):

Wherein L is a leaving group such as halo (typically chloro, bromo oriodo) or a sulphonate (typically methanesulphonate) and R¹, R², R³, R⁴,R⁵, n and m are as defined for compounds of formula (I).

The reaction of compounds of formula (XIII) and (VI) is optionallyeffected in the presence of an organic base, such as a trialkylamine,for example triethylamine, and in a suitable solvent, for example anamide such as DMF.

Compounds of formula (XIII) may be prepared by methods well known in theart. Thus for example they may be readily prepared by a person skilledin the art, from the corresponding halide of formula (XIV):

wherein Ar is as hereinbefore defined and Y is halo eg. bromo.

The conversion of a compound of formula (XIV) to a compound of formula(XIII) may be effected by reaction with sodium azide in a suitablesolvent, for example N,N-dimethylformamide, to give the correspondingcompound wherein Y denotes N₃. The carbonyl group may then be reduced tothe corresponding alcohol by any suitable method, for example bytreatment with borane, in the presence of a chiral catalyst, such as(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole,in a suitable solvent such as tetrahydrofuran. The azide group may bereduced to the corresponding amine group by any suitable method, forexample by catalytic hydrogenation in the presence of a catalyst such aspalladium/charcoal or platinum oxide.

Further details concerning preparation of compounds (XIII) wherein Ar isa group (iv) in DE3524990; concerning the preparation of compounds(XIII) wherein Ar is a group (i), (vii), and (xv) in EP-A-162576;concerning the preparation of compounds (XIII) wherein Ar is a group(iii) in EP-A-22054; concerning the preparation of compounds (XIII)wherein Ar is a group (x) in GB2165542 and concerning the preparation ofcompounds (XIII) wherein Ar is a group (c) in GB2230523.

Compounds of formula (XIV) are known compounds or may readily beprepared by those skilled in the art using known methods.

In a further process (c) a compound of formula (I), may be prepared byreacting a compound of formula (XV):

wherein L is a leaving group as hereinbefore defined, with an amine offormula (XVI):

The reaction may be effected using conventional conditions for suchdisplacement reactions.

Compounds of formula (XV) may be prepared by methods known in the art.

Thus for example, compounds (XV) wherein Ar is a group (xv) may beprepared as described in EP-A-147719.

Compounds of formula (XVI) may be prepared by reacting a compound offormula (VI) with an amine R²⁶NH₂, followed by removal of the protectinggroup R²⁶.

According to a further process (d) compounds of formula (I) wherein oneof R⁴ and R⁵ represents hydrogen may be prepared by;

(i) reacting a compound of formula (XIII):

Wherein Ar is as hereinbefore defined and R³⁴ represents hydrogen or achiral auxiliary, with a compound of formula (XVII):

wherein R¹, R², R³, R⁴, n and m are as hereinbefore defined;

followed where necessary by removal of the chiral auxiliary R³⁴;

or (ii) reacting a compound of formula (XVIII):

wherein Ar is as hereinbefore defined; with an amine of formula (XVI):

as hereinbefore defined,

under conditions suitable to effect reductive amination, for example inthe presence of a reducing agent such as a borohydride, trypicallytetramethylammonium (triacetoxy)borohydride.

When process (di) involves use of a chiral auxiliary this is preferablythe S-isomer and/or the R-isomer of phenyl glycinol. The reaction may beeffected as described in International Application Number WO/0196278.

A compound of formula (XVII) may be prepared by methods known in theart, for example via a compound of formula (VI) as hereinbefore defined.

A compound of formula (XVIII) may also be prepared from a correspondingalcohol, which may itself be obtained from a compound of formula (XV) ashereinbefore defined, using standard methods well known to those skilledin the art.

It will be appreciated that in any of the routes (a) to (d) describedabove, the precise order of the synthetic steps by which the variousgroups and moieties are introduced into the molecule may be varied. Itwill be within the skill of the practitioner in the art to ensure thatgroups or moieties introduced at one stage of the process will not beaffected by subsequent transformations and reactions, and to select theorder of synthetic steps accordingly. It will also be appreciated thatin the processes (b), (c) and (d) appropriate protecting groups may beemployed if necessary and/or desired and removed at any suitable stageof the synthesis, eg. in the last stage, as described in process (a).

The enantiomeric compounds of the invention may be obtained (i) byseparation of the components of the corresponding racemic mixture, forexample, by means of a chiral chromatography column, enzymic resolutionmethods, or preparing and separating suitable diastereoisomers, or (ii)by direct synthesis from the appropriate chiral intermediates by themethods described above.

Optional conversions of a compound of formula (I), to a correspondingsalt may conveniently be effected by reaction with the appropriate acidor base. Optional conversion of a compound of formula (I), to acorresponding solvate or physiologically functional derivative may beeffected by methods known to those skilled in the art.

According to a further aspect, the present invention provides novelintermediates for the preparation of compounds of formula (I), forexample:

compounds of formula

For a better understanding of the invention, the following Examples aregiven by way of illustration.

SYNTHETIC EXAMPLES

Throughout the examples, the following abbreviations are used:

LC: Liquid Chromatography

LCMS: Liquid Chromatography Mass Spectrometry

HPLC: High Performance Liquid Chromatography

RT: retention time

DCM: dichloromethane

IMS: industrial methylated spirits

EtOAc: ethyl acetate

EtOH: ethanol

DMAP: N,N-Dimethylaminopyridine

DMF: N,N-Dimethylformamide

MeOH: methanol

THF: tetrahydrofuran

IMS: Industrial methylated spirits

h: hour(s)

min: minute(s)

All temperatures are given in degrees celcius.

Flash silica gel refers to Merck Art No. 9385; silica gel refers toMerck Art No. 7734

Biotage refers to prepacked silica gel cartridges containing KP-Sil runon flash 12i chromatography module.

Solid Phase Extraction (SPE) columns are pre-packed cartridges used inparallel purifications, normally under vacuum. These are commerciallyavailable from Varian.

SCX cartridges are Ion Exchange SPE columns where the stationary phaseis polymeric benzene sulfonic acid. These are used to isolate amines.

LC was conducted on a Luna C18(2) column (5 cm×2.0 mm ID) eluting with0.05% v/v trifluoroacetic acid in water (solvent A) and 0.05% v/vtrifluoroacetic acid in acetonitrile (solvent B) using the followingelution gradient 0.00-8.00 min 0% B, 8.00-8.01 min 95% B, 8.01-10.00 min0% B at a flow rate of 1.0 ml/min with a column temperature of 40° C.

LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm×4.6 mm ID)eluting with 0.1% HCO₂H and 0.01M ammonium acetate in water (solvent A)and 0.05% HCO₂H 5% water in acetonitrile (solvent B), using thefollowing elution gradient 0.0-7 min 0% B, 0.7-4.2 min 100% B, 4.2-5.3min 0% B, 5.3-5.5 min 0% B at a flow rate of 3 mL/min. The mass spectrawere recorded on a Fisons VG Plafform spectrometer using electrospraypositive and negative mode (ES+ve and ES−ve).

Preparative mass directed HPLC was conducted on a Waters FractionLynxsystem comprising of a Waters 600 pump with extended pump heads, Waters2700 autosampler, Waters 996 diode array and Gilson 202 fractioncollector on a 10 cm×2.54 cm ID ABZ+column, eluting with 0.1% formicacid in water (solvent A) and 0.1% formic acid in acetonitrile (solventB), using the following elution gradient: 0.0-1.0 min 15% B, 1.0-10.0min 55% B, 10.0-14.5 min 99% B, 14.5-14.9 min 99% B, 14.9-15.0 min 15% Bat a flow rate of 20 ml/min and detecting at 200-320 nm at roomtemperature. Mass spectra were recorded on Micromass ZMD massspectrometer using electrospray positive and negative mode, alternatescans. The software used was MassLynx 3.5 with OpenLynx and FractionLynxoptions.

EXAMPLE 18-Hydroxy-5-((1R)-1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)quinolin-2(1H)-oneacetate (i)8-(Benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]quinolin-2(1H)-one

A solution of [(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]-oxazaborole] (1M, 424 μL) in THF (2 ml) was added to boranedimethylsulfide complex (2M, 212.7 μl) in THF (15 ml) and stirred at 0°C. for 10 min. The reaction mixture was cooled to −10° C. and treatedwith a solution of 8-benzyloxy-5-bromoacetylcarbostyril (EP 147719A2)(791 mg) in THF (16 ml) over 20 min. Further borane dimethylsulfidecomplex (1.28 ml) was added over 4 h at 0° C. The reaction mixture wasstirred for a further hour at 0° C. prior to quenching with methanol and1N HCl(aq). The reaction mixture was partitioned between water and ethylacetate. The organic phase was dried and concentrated in vacuo. Theresidue was triturated with hexane-ethyl acetate to afford the titlecompound (700 mg). Rf (EtOAc) 0.47

(ii)8-(Benzyloxy)-5-[(1R)-2-bromo-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]quinolin-2(1H)-one

A suspension of8-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]quinolin-2(1H)-one (100 mg)and pyridinium tosylate (14 mg) in dry DCM (2 ml) was treated with2,3-dihydropyran (61.2 μl) and stirred at 22° C. for 18 h. The reactionmixture was concentrated in vacuo and purified by chromatography(Hexane-EtOAc 2:1, biotage) to give the title compound (77 mg). Rf[EtOAc-Hexane (1:1)] 0.54

(iii)8-(Benzyloxy)-5-[(1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]quinolin-2(1H)-one

8-(Benzyloxy)-5-[(1R)-2-bromo-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]quinolin-2(1H)-one(100 mg), N-benzyl-6-(4-phenylbutoxy)hexan-1-amine (Tetrahedron Letters.1994, 35, 9375) (112 mg) and diisopropylethylamine (77 μl) were heatedin a reacti-vial at 120° C. for 4 h prior to cooling to roomtemperature. The mixture was purified by chromatography (Hexane-EtOAc2:1, biotage) afforded the title compound (85 mg). LCMS RT=3.46 min

(iv)8-(Benzyloxy)-5-((1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)quinolin-2(1H)-one

A solution of8-(benzyloxy)-5-[(1R)-2-(benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]quinolin-2(1H)-one(80 mg) in acetic acid (4 ml), THF (2 ml) and water (1 ml) was heated at80° C. for 17 h prior to concentration in vacuo. The residue waspurified by chromatography (Hexane-EtOAc 2:1, biotage) to give the titlecompound (33.5 mg).

LCMS RT=3.22 min

(v)8-Hydroxy-5-((1R)-1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)quinolin-2(1H)-oneacetate

A solution of8-(benzyloxy)-5-((1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)quinolin-2(1H)-one(33 mg) in ethanol (15 ml) and acetic acid (0.4 ml) was stirred underhydrogen in the presence of palladium on charcoal (10 mg) for 4 h. Thereaction mixture was filtered and concentrated in vacuo. The residue waspurified by chromatography (SPE, gradient from DCM to DCM-MeOH—NH₃(aq)100:10:1) to give the title compound (19.5 mg).

LCMS RT=2.66 min ES+ve 452 (MH)⁺

EXAMPLE 23-{4-[(6-{[(2R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}hexyl)oxy]butyl}benzenesulfonamideacetate (i) 6-Bromohexyl but-3-ynyl ether

A mixture of 50% w/v aqueous sodium hydroxide (2500 ml),1,6-dibromohexane (2610 g) and tetra-butylammonium bromide (25 g) waswarmed to 50° C., with stirring. But-3-yn-1-ol (500 g) was then added tothe reaction mixture at such a rate as to ensure the content'stemperature did not exceed 65° C. The reaction was left at 50° C.overnight before being cooled to room temperature. Tert-butyl methylether (2500 ml) and brine (2000 ml) was added to the cooled mixture andthe layers allowed to separate. The ethereal layer was washed with water(2×2000 ml), brine (1×2000 ml), and then dried over anhydrous MgSO₄. Thesolution was filtered and concentrated under reduced pressure to givecrude product as a liquid. This was further purified by fractionaldistillation using a 60 cm vacuum jacketed Vigreux column at ca. 0.5mbar. The product was obtained in the fraction which boiled at 92-98°C., to give the title compound (518 g), LC RT=6.16 min.

(ii) 3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}benzenesulfonamide

A mixture of 3-bromo-benzenesulfonamide (625 g), 6-bromohexyl but-3-ynylether (850.1 g), bis(triphenylphosphine)palladium (II) chloride (62.5g), triphenylphosphine (18.1 g) and triethylamine (536.3 g) intetrahydrofuran (6250 ml) was stirred under an atmosphere of nitrogenfor 20 min. Copper (I) iodide (12.5 g) was then added to give a darkred/brown mixture that was heated to 50° C. for 23 h. The reactionmixture was then cooled to room temperature and filtered through a shortsilica pad (1000 g). The pad was washed with additional tetrahydrofuran(15.6L) and the resulting solution then concentrated under reducedpressure to give crude product (1382 g) as a viscous oil. This waspurified by chromatography (7 kg silica) eluting with petroleumether-ethyl acetate (5:1) followed by petroleum ether-ethyl acetate(2:1) to give the title compound (932.9 g) as an oil, LC RT=5.69 min.

(iii) 3-{4-[(6-Bromohexyl)oxy]butyl}benzenesulfonamide

3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}benzenesulfonamide (627 g) in IMS(1900 ml) was stirred with activated charcoal (314 g) at roomtemperature for 2 h and then filtered through a short pad of Celite. Thefilter pad was washed with IMS (4300 ml) and the filtrate transferred toa hydrogenation vessel. 5% Platinum on Charcoal (520.1 g, ˜50% water)was added and the reaction mixture was then stirred under an atmosphereof hydrogen (0.2 bar) at 20° C. for 6 h. The mixture was then filteredthrough a short pad of Celite and concentrated under reduced pressure togive the title compound (499 g) as a solid, LC RT=5.66 min.

(iv) 3-(4-{[6-(Benzylamino)hexyl]oxy}butyl)benzenesulfonamide

3-[4-(6-Bromo-hexyloxy)-butyl]benzenesulfonamide (1.0 g) in toluene (4ml) was added dropwise to benzylamine (0.65 g) and the resulting mixtureheated at 80° C. for 6 h. The mixture was then cooled and 20% aqueoussodium hydroxide solution (50 ml) was added. The resulting mixture wasextracted with ethyl acetate and the combined organic layers evaporatedto dryness in vacuo. The residual oil was then purified bychromatography (DCM-IMS-NH₃(aq) 100:10:1) to give the title compound(0.54 g) LC RT=3.89 min.

(v)3-(4-{[6-(Benzyl{(2R)-2-[8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl]-2-acetyl}amino)hexyl]oxy}butyl)benzenesulfonamide

A solution of 8-benzyloxy-5-bromoacetylcarbostyril (100 mg) (EP147719A2) in dry DMF was treated with3-(4-{[6-(benzylamino)hexyl]oxy}butyl)benzenesulfonamide (172 mg) anddiisopropylethylamine (94.5 μl) and stirred at 40° C. for 2 h prior toconcentration in vacuo. The residue was purified by chromatography (SPE,gradient from DCM to DCM-MeOH—NH₃(aq) 100:10:1) to give the titlecompound (56 mg).

LCMS RT=2.95 min.

(vi)3-(4-{[6-(Benzyl{(2R)-2-[8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)benzenesulfonamide

A solution of [(R)-tetrahyro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]-oxazaborole] (108 μL) in THF (1 ml) was added to boranedimethylsulfide complex in THF (2M, 54 μl) and stirred at 0° C. for 10min. The reaction mixture was cooled to −10° C. and treated with asolution of3-(4-{[6-(benzyl{(2R)-2-[8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl]-2-acetyl}amino)hexyl]oxy}butyl)benzenesulfonamide(64 mg) in THF (3 ml). The reaction mixture was stirred for 16 h at 0°C. prior to quenching with 2N HCl(aq). The reaction mixture waspartitioned between 2N HCl(aq) and ethyl acetate. The organic phase wasdried and concentrated in vacuo. The residue was purified bychromatography (biotage, DCM-MeOH—NH₃(aq) 400:10:1) to give the titlecompound (10 mg).

LCMS RT=2.91 min.

(vii)3-{4-[(6-{[(2R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}hexyl)oxy]butyl}benzenesulfonamideacetate

A solution of3-(4-{[6-(Benzyl{(2R)-2-[8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)benzenesulfonamide(10 mg) in ethanol (10 ml) and acetic acid (0.1 ml) was stirrer underhydrogen in the presence of palladium on charcoal (5 mg) for 2 h. Thereaction mixture was filtered and concentrated in vacuo. The residue waspurified by chromatography (SPE, gradient from DCM to DCM-MeOH—NH₃(aq)100:10:1) and freeze-dried from water-acetic acid to give the titlecompound (5.8 mg).

LCMS RT=2.28 min ES+ve 532 (MH)⁺

EXAMPLE 35-Hydroxy-8-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-2H-1,4-benzoxazin-3(4H)-oneacetate (i)5-(Benzyloxy)-8-(2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)-2H-1,4-benzoxazin-3(4H)-one

A solution of5-(benzyloxy)-8-(dihydroxyacetyl)-2H-1,4-benzoxazin-3(4H)-one (DE3134590 A1) (150 mg) in dry DCM (2 ml) was treated with acetic acid andN-benzyl-6-(4-phenylbutoxy)hexan-1-amine (320 mg) (Tetrahedron Letters.1994, 35, 9375) and stirred for 4 hr. Sodium triacetoxyborohydride (216mg) was added and the reaction mixture stirred at room temperature for 3days. Sodium borohydride (35 mg) in methanol (2 ml) was added andstirring continued for a further 2 h. The reaction mixture was quenchedwith water and partitioned between water and DCM. The organic phase wasdried and concentrated in vacuo. The residue was purified bychromatography (Hexane-EtOAc, SPE) to give the title compound as amixture with5-(benzyloxy)-8-({benzyl[6-(4-phenylbutoxy)hexyl]amino}acetyl)-2H-1,4-benzoxazin-3(4H)-one(81.6 mg).

LCMS RT=3.24 min.

(ii)5-Hydroxy-8-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-2H-1,4-benzoxazin-3(4H)-oneacetate

A solution of5-(benzyloxy)-8-(2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)-2H-1,4-benzoxazin-3(4H)-one(82 mg) in ethanol (10 ml) and ethyl acetate (2 ml) was stirrer underhydrogen in the presence of palladium on charcoal (50 mg) for 8 h. Thereaction mixture was filtered and concentrated in vacuo. Mass directedauto-preparative chromatography afforded the title compound (13.7 mg).LCMS RT=2.62 min ES+ve 456 (MH)⁺

EXAMPLE 43-{4-[(6-{[2-Hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}hexyl)oxy]butyl}benzenesulfonamide(i)3-(4-{[6-(Benzyl{2-[5-(benzyloxy)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)benzenesulfonamide

Prepared by methods similar to that described for Example 3i as amixture with3-(4-{[6-(benzyl{2-[5-(benzyloxy)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl]-2-acetyl}amino)hexyl]oxy}butyl)benzenesulfonamide(22.3 mg).

LCMS RT=2.83 min

(ii)3-{4-[(6-{[2-Hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

Prepared by methods similar to that described for Example 3ii LCMSRT=2.32 min

ES+ve 536 (MH)⁺

EXAMPLE 54-Hydroxy-7-((1R)-1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-1,3-benzothiazol-2(3H)-oneformate (i) 7-Acetyl-4-methoxy-1,3-benzothiazol-2(3H)-one

A solution of 4-methoxy-1,3-benzothiazol-2(3H)-one (DE 3017977 A1) (1.92g) in dry dichloromethane (50 ml) was cooled to ˜5° C. under nitrogen.Acetyl chloride (1.43 ml) and aluminium chloride (3.43 g) were added inone portion, and stirred for 2 h at RT. The reaction was quenchedcarefully with water, followed by addition of 2N HCl anddichloromethane. The aqueous layer was extracted with dichloromethane,and the combined organic layers were washed with brine and dried(Na₂SO₄) and evaporated in vacuo to give the title compound (1.92 g).LCMS RT=2.50 min

(ii) 7-Acetyl-4-hydroxy-1,3-benzothiazol-2(3H)-one

A mixture of 7-acetyl4-methoxy-1,3-benzothiazol-2(3H)-one (1.2 g),pyridine hydrochloride (2.77 g), in dry 1-methyl-2-pyrrolidone(6 ml),was heated at 190° C. in a microwave reactor for 90 min. The reactionmixture was cooled to room temperature, and diluted with water. Theprecipitated solid was collected by filtration, washed with water anddried under vacuum at 40° C. to give the title compound (1.07 g). LCMSRT=2.46 min.

(iii) 7-Acetyl-4-(benzyloxy)-1,3-benzothiazol-2(3H)-one

To a solution of 7-acetyl-4-hydroxy-1,3-benzothiazol-2(3H)-one (153 mg),in dry THF (3 ml) and dry DMF (0.5 ml) under nitrogen, was addedN,N-diisopropylethylamine (0.13 ml) and benzyl bromide (0.09 ml), andthe mixture stirred for 72 h. Water (10 ml) was added and the mixtureextracted with ethyl acetate. The organic phases were combined, washedwith brine, dried (MgSO₄), and evaporated in vacuo. The residue waspurified on a 5 g silica SPE cartridge, eluting with a stepped gradientof 10% to 50% ethyl acetate-cyclohexane mixtures, to give the titlecompound (68 mg). LCMS RT=3.14 min.

(iv) 4-(Benzyloxy)-7-(bromoacetyl)-1,3-benzothiazol-2(3H)-one

To a solution of 7-acetyl-4-(benzyloxy)-1,3-benzothiazol-2(3H)-one (68mg) in dry THF (3 ml) under nitrogen, was added phenyltrimethylammoniumtribromide (90 mg) and the mixture heated at 80° C. under nitrogen for 2h. The mixture was diluted with water, extracted with ethyl acetate,dried (MgSO₄), filtered and evaporated in vacuo. The residue waspurified on a 5 g silica SPE cartridge, eluting with stepped gradient of10% to 100% ethyl acetate-cyclohexane mixtures, to give the titlecompound (49 mg).

LCMS RT=3.13 min.

(v)4-(Benzyloxy)-7-[(1R)-2-bromo-1-hydroxyethyl]-1,3-benzothiazol-2(3H)-one

A solution of [(R)-tetrahyro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]-oxazaborole] (22 μl of 1M in toluene) in dry THF(1 ml) wascooled to −5° C., stirring under nitrogen. Borane-methyl sulfide complex(2M solution in THF, 11 μl) was added and stirred for 10 min at −5° C. Asolution of 4-(benzyloxy)-7-(bromoacetyl)-1,3-benzothiazol-2(3H)-one (47mg) in dry THF (1.5 ml) was added dropwise and then another 66 μl ofborane-methyl sulfide complex (2M solution in THF). The reaction mixturewas left for 72 h at less than 5° C. and then partitioned between 2N HCland ethyl acetate. The organic solution was dried (MgSO₄), filtered andevaporated in vacuo. The residue was purified on a 5 g silica SPEcartridge, eluting with a stepped gradient of 10% to 25% ethylacetate-cyclohexane mixtures to give the title compound (33 mg). LCMCRT=3.19 min.

(vi)4-(Benzyloxy)-7-{(1R)-2-bromo-1-[tetrahydro-2H-pyran-2-yloxy]ethyl}-1,3-benzothiazol-2(3H)-one

To a stirred solution of4-(benzyloxy)-7-[(1R)-2-bromo-1-hydroxyethyl]-1,3-benzothiazol-2(3H)-one(31 mg) in dry DCM (5 ml) under nitrogen, was added pyridiniump-toluenesulphonate (5 mg), followed by 3,4-dihydro-2H-pyran (30 μl).The mixture was evaporated in vacuo after 18 h and purified on a 2 gsilica SPE cartridge, eluting with a stepped gradient 10% to 100%DCM-cyclohexane mixtures, to give the title compound (42 mg). LCMSRT=3.72 and 3.78 min.

(vii)4-(Benzyloxy)-7-{(1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-[tetrahydro-2H-pyran-2-yloxy]ethyl}-1,3-benzothiazol-2(3H)-one

A mixture of4-(benzyloxy)-7-{(1R)-2-bromo-1-[tetrahydro-2H-pyran-2-yloxy]ethyl}-1,3-benzothiazol-2(3H)-one(42 mg), N,N-diisopropylethylamine (32 μl), andN-benzyl-6-(4-phenylbutoxy)hexan-1-amine (Tetrahedron Letters. 1994, 35,9375) (47.5 mg), was heated at 120° C. in a reacti-vial for 18 h. Themixture was dissolved in DCM and purified on a 12 g biotage cartridge,eluting with 15% ethyl acetate-cyclohexane mixture to give the titlecompound (10 mg). LCMS RT=3.62 and 3.66 min.

(viii)4-(Benzyloxy)-7-((1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-hydroxyethyl)-1,3-benzothiazol-2(3H)-one

To a solution of4-(benzyloxy)-7-{(1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-[tetrahydro-2H-pyran-2-yloxy]ethyl}-1,3-benzothiazol-2(3H)-one(10 mg) in dry DCM (1 ml) and methanol (0.1 ml) stirring under nitrogen,was added p-toluenesulphonic acid (10 mg). After 18 h 2N sodiumbicarbonate was added and the mixture extracted with DCM. The organicsolution was diluted with cyclohexane and the mixture purified on a 5 gsilica SPE cartridge to give the title compound (7.4 mg). LCMS RT=3.13min.

(ix)4-Hydroxy-7-((1R)-1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-1,3-benzothiazol-2(3H)-oneformate

4-(Benzyloxy)-7-((1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)-1,3-benzothiazol-2(3H)-one(7.4 mg) was dissolved in 98% formic acid (0.5 ml)and palladium blackcatalyst (4 mg) added. After stirring for 8 h, the catalyst was removedby filtration through celite and the filtrate evaporated in vacuo. Theresidue was purified on mass directed autoprep, to give the titlecompound (0.51 mg). LCMS RT=2.95 min. ES+ve 459 (M+H)⁺

EXAMPLE 64-Hydroxy-7-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-1,3-benzothiazol-2(3H)-oneformate (i) 7-Acetyl-2-oxo-2,3-dihydro-1,3-benzothiazol-4-yl benzylcarbonate

A mixture of 7-acetyl-4-hydroxy-1,3-benzothiazol-2(3H)-one (209 mg) indry THF (5 ml) and DCM (5 ml) with pyridine (0.2 ml), stirring undernitrogen, was cooled to −10° C. and benzylchloroformate (0.37 mls) wasadded. After 18 h stirring at room temperature, the mixture was dilutedwith water and extracted into DCM. The solution was dried (MgSO₄),filtered, and evaporated in vacuo. The residue was purified on a 10 gsilica SPE cartridge, eluting with a stepped gradient of 25% to 100%ethyl acetate-cyclohexane mixtures, to give the title compound (280 mg).LCMS RT=3.19 min.

(ii) Benzyl 7-(bromoacetyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-4-ylcarbonate

To a solution of 7-acetyl-2-oxo-2,3-dihydro-1,3-benzothiazol-4-yl benzylcarbonate (280 mg) in dry THF (20 ml) stirring under nitrogen, was addedphenyltrimethylammonium tribromide (330 mg). The mixture was heated at80° C. for 2 h and then diluted with water, extracted with ethylacetate, dried (MgSO₄), filtered, and evaporated in vacuo. The residuewas purified on a 40 g silica biotage cartridge and eluted with 20%ethyl acetate-cyclohexane to give the title compound (186 mg). LCMSRT=3.43 min.

(iii)7-({Benzyl[6-(4-phenylbutoxy)hexyl]amino}acetyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one

To a solution of benzyl7-(bromoacetyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-4-yl carbonate (50mg) in dry DMF (1 ml) stirring under nitrogen was addedN-benzyl-6-(4-phenylbutoxy)hexan-1-amine (Tetrahedron Letters. 1994, 35,9375) (60 mg) and N,N-diisopropylethylamine (32 μl). After stirring at40° C. for 2 h, 2N HCl was added and the mixture extracted with ethylacetate. The solution was dried (MgSO₄), filtered and evaporated invacuo. The residue was purified on a 5 g silica SPE cartridge, elutingwith a stepped gradient of 2% to 10% methanol-dichloromethane mixturesto give the title compound (50 mg). LCMS RT=3.14 min.

(iv)4-Hydroxy-7-({[6-(4-phenylbutoxy)hexyl]amino}acetyl)-1,3-benzothiazol-2(3H)-one

A solution of7-({benzyl[6-(4-phenylbutoxy)hexyl]amino}acetyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one(100 mg) in dry ethanol (10 ml) and acetic acid (0.5 ml) was added to10% Pd/C catalyst (40 mg) and stirred under hydrogen for 20 h. Thecatalyst was collected by filtration through celite and the filtrateevaporated in vacuo. The residue was purified on SCX and then silica SPEcartridge, eluting with a stepped gradient of 1-10%methanol-dichloromethane mixtures, to give the title compound (9 mg).LCMS RT=2.81 min.

(v)4-Hydroxy-7-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-1,3-benzothiazol-2(3H)-oneformate

Sodium borohydride (4 mg) was added to a solution of4-hydroxy-7-({[6-(4-phenylbutoxy)hexyl]amino}acetyl)-1,3-benzothiazol-2(3H)one (9 mg) in dry ethanol (2 ml). The mixture was stirred under nitrogenfor 2 h, and then quenched with water and evaporated in vacuo. Theresidue was purified by mass directed autoprep. to give the titlecompound (1.5 mg). LCMS RT=2.74 min, ES+ve 459 (M+H)⁺

EXAMPLE 73-{4-[(6-{[(2R)-2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamideformate i) 2-Azido-1-[4-(benzyloxy)-3-fluorophenyl]ethanone

A solution of 2-bromo-1-[4-(benzyloxy)-3-fluorophenyl]ethanone (J. Med.Chem. 1980, 23, 738-744) (1 g) in dry DMF (2.5 mL) was cooled to 15° C.and treated portionwise with sodium azide (220 mg). After completeaddition the reaction mixture was stirred for a further 1 h. Thereaction mixture was partitioned between EtOAc and water. The organicphase was washed with water and the combined aqueous phase backextracted with EtOAc. The combined organic phase was washed with sat.NaHCO_(3(aq)) three times and the combined washes back extracted withEtOAc. The combined organic phase was washed with brine, dried andconcentrated in vacuo. The residue was purified by column chromatographyon silica, eluting with hexane-EtOAc (4:1 and 2:1) to give the titlecompound (810 mg). LCMS RT=3.61 min.

ii) (1R)-2-Azido-1-[4-(benzyloxy)-3-fluorophenyl]ethanol

Borane-dimethylsulphide solution in THF (2M, 0.03 mL) was added to asolution of (R)-2-methyl-CBS-oxazaborolidine in toluene (1M, 0.06 mL) at0° C. with stirring. The reaction mixture was stirred for 15 min priorto the dropwise addition of a solution of2-azido-1-[4-(benzyloxy)-3-fluorophenyl]ethanone (100 mg) in THF.Further Borane-dimethylsulphide in THF (2M, 0.03 mL) was added dropwiseand the reaction mixture stirred at 0° C. for 2 h. 2M HCl_((aq)) (2 mL)was added dropwise and the reaction mixture stirred for 10 min prior topartitioning the reaction mixture between ether and water. The organicphase was washed twice with 2M HCl_((aq)), three times with sat.NaHCO_(3(aq)), water and brine. The organic phase was dried andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel, eluting with DCM to give the title compound (470 mg).LCMS RT=3.36 min.

iii) (1R)-2-Amino-1-[4-(benzyloxy)-3-fluorophenyl]ethanol

A solution of (1R)-2-azido-1-[4-(benzyloxy)-3-fluorophenyl]ethanol (410mg) in THF (8 mL) and water (2 mL) was treated with PPh₃ (410 mg) andstirred for 1 h prior to addition of further with PPh₃ (220 mg). Afterstirring for a further 4 h the reaction mixture was concentrated invacuo and the residue partitioned between EtOAc and water. The organicphase was washed three times with 5% NaHCO_(3(aq)) dried andconcentrated in vacuo. The residue was purified by chromatography onsilica gel, eluting with DCM, 1% MeOH in DCM, 2% MeOH in DCM, 5% MeOHcontaining 0.5% Et₃N in DCM, and finally 20% MeOH containing 1% Et₃N inDCM) to give the title compound (260 mg). LCMS RT=2.16 min.

iv) 4-[(1R)-2-Amino-1-hydroxyethyl]-2-fluororhenol

Palladium on carbon (10% Pd by weight, wet, 50 mg) was flushed withnitrogen and treated with a solution of(1R)-2-amino-1-[4-(benzyloxy)-3-fluorophenyl]ethanol (500 mg) in ethanol(25 mL), EtOAc (25 mL) and acetic acid (10 mL). The reaction mixture wasstirred under hydrogen for 5 h prior to flushing the reaction mixturewith nitrogen and filtering to remove the catalyst and concentrating invacuo. The residue was purified by chromatography (SCX, eluted with DCM,MeOH and DCM-MeOH—NH₃(aq) 100:10:1) to give the title compound (308 mg).δ_(H) (400 MHz, CD₃OD) 7.05 (1H, dd, J 2, 12 Hz), 6.94 (1H, dd, J 2, 9Hz), 6.86 (1H, t, J 9 Hz), 4.54 (1H, dd, J 5, 8 Hz), 2.78 (1H, d, J 5Hz), 2.77 (1H, d, J 8 Hz).

v)3-{4-[(6-{[(2R)-2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamideformate

A stirred solution of 4-[(1R)-2-amino-1-hydroxyethyl]-2-fluorophenol (45mg), diisopropylethylamine (0.06 ml) and3-{4-[(6-bromohexyl)oxy]butyl}benzenesulfonamide (86 mg) inN,N-dimethylformamide (1 ml) under nitrogen was heated to 50° for 18 h.The mixture was cooled to 20°, the solvent evaporated in vacuo and theresidue purified by mass-directed autopreparative HPLC to give the titlecompound (36 mg). LCMS RT=2.37 min, ES+ve 483 (MH)⁺.

EXAMPLE 83-(4-{[6-({2-Hydroxy-2-[5-hydroxy-6-(hydroxymethyl)pyridin-2-yl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideformate

A stirred solution of2-amino-1-(2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)ethanol (100 mg)(EP220054A2), diisopropylethylamine (0.08 ml) and3-{4-[(6-bromohexyl)oxy]butyl}benzenesulfonamide (120 mg) inN,N-dimethylformamide (2 ml) under nitrogen was heated to 50° for 18 h.The mixture was cooled to 20° and the solvent evaporated in vacuo. Theresidue was dissolved in acetic acid (4 ml) and water (2 ml) and washeated to 70° for 18 h. The mixture was cooled to 20°, the solventevaporated in vacuo and the residue purified by mass-directedautopreparative HPLC to give the title compound (22 mg). LCMS RT=2.23min, ES+ve 496 (MH)⁺.

EXAMPLE 93-[4-({6-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]hexyl}oxy)butyl]benzenesulfonamideformate i)N-[2-Hydroxy-5-((1R)-1-hydroxy-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethyl)phenyl]methanesulfonamide

A solution of N-[5-(bromoacetyl)-2-hydroxyphenyl]methanesulfonamide (J.Med. Chem. 1967, 10, 462-72) (1.15 g) in dry DMF (30 mL) was treatedwith diisopropylethylamine (1.06 mL) and (S)-phenylglycinol (474 mg) andthe reaction mixture stirred at room temperature for 4 h. The reactionmixture was concentrated in vacuo and the residue re-suspended inmethanol (50 mL). The reaction mixture was cooled to 0° C. and treatedwith CaCl₂ (1.27 g). The reaction mixture was stirred at 0° C. for 30min prior to portionwise addition of NaBH₄ (218 mg) ensuring that thetemperature did not rise above 10° C. After complete addition thereaction mixture was allowed to warm to room temperature and stirred fora further 74 h. The reaction mixture was concentrated in vacuo and theresidue partitioned between EtOAc and water. The organic phase was driedand concentrated in vacuo. The mixture was purified by chromatography(SPE, gradient from DCM to DCM-MeOH—NH₃(aq) 100:10:1) afforded the titlecompound (85 mg). LCMS RT=2.48 min

ii)N-{5-[(1R)-2-Amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide

Palladium hydroxide (40 mg, 50% water) was flushed with nitrogen andtreated with a solution ofN-[2-hydroxy-5-((1R)-1-hydroxy-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethyl)phenyl]methanesulfonamide(400 mg) in methanol (80 mL) and acetic acid (0.5 mL). The reactionmixture was stirred under hydrogen for 16 h prior to flushing thereaction mixture with nitrogen and filtering to remove the catalyst andconcentrating in vacuo. The residue was purified by chromatography(OASIS, eluted with water, 5% MeOH in water 50% MeOH in water and MeOH)to give the title compound (182 mg). δ_(H) (400 MHz, CD₃OD) 7.38 (1H, d,J 2 Hz), 7.12 (1H, dd, J 2, 8 Hz), 6.90 (1H, d, J 8 Hz), 4.78 (1H, dd, J2, 10 Hz), 3.08 (1H, dd, J 2, 15 Hz), 2.98 (1H, bd, J 10 Hz), 2.93 (3H,s).

iii)3-[4-({6-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]hexyl}oxy)butyl]benzenesulfonamideformate

A stirred solution of1-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide(65 mg), diisopropylethylamine (0.06 ml) and3-{4-[(6-bromohexyl)oxy]butyl}benzenesulfonamide (86 mg) inN,N-dimethylformamide (1 ml) under nitrogen was heated to 50° for 48 h.The mixture was cooled to 20°, the solvent evaporated in vacuo and theresidue purified by mass-directed autopreparative HPLC to give the titlecompound (12 mg). LCMS RT=2.31 min ES+ve 558 (MH)⁺.

EXAMPLE 103-{3-[(7-{[(2R)-2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]amino}heptyl)oxy]propyl}benzenesulfonamideformate

Prepared using methods similar to those described in Example 7.

LCMS RT=2.37 min, ES+ve 483 (MH)⁺.

EXAMPLE 113-(3-{[7-({2-Hydroxy-2-[5-hydroxy-6-(hydroxymethyl)pyridin-2-yl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamideformate

Prepared using methods similar to those described in Example 8.

LCMS RT=2.22 min, ES+ve 496 (MH)⁺.

EXAMPLE 123-[3-({7-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]heptyl}oxy)propyl]benzenesulfonamideformate

Prepared using methods similar to those described in Example 9.

LCMS RT=2.33 min, ES+ve 558 (MH)⁺.

EXAMPLE 133-{3-[(7-{[(2R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}heptyl)oxy]propyl}benzenesulfonamideacetate i)5-[(1R)-2-(Benzylamino)-1-hydroxyethyl]-8-(benzyloxy)quinolin-2(1H)-one

8-(Benzyloxy)-5-[(2R)-oxiran-2-yl]quinolin-2(1H)-one (0.102 g) (WO9525104), was dissolved in benzylamine (0.5 ml) and heated in amicrowave oven for 15 min at 150° C. Excess benzylamine was removed byevaporation on a rotary evaporator and the residue was purified on asilica SPE cartridge using methanol-dichloromethane-0.880 ammoniamixtures, to give the title compound (106 mg) LCMS RT=2.30 min

ii)3-(3-{[7-(Benzyl{(2R)-2-[8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl]-2-hydroxyethyl}amino)heptyl]oxy}propyl)benzenesulfonamide

5-[(1R)-2-(Benzylamino)-1-hydroxyethyl]-8-(benzyloxy)quinolin-2(1H)-one(48 mg) was dissolved in acetonitrile (2 ml). N,N-diisopropylethylamine(0.042 ml), and 3-{3-[(7-bromoheptyl)oxy]propyl}benzenesulfonamide (43mg) were added to the solution, which was heated at reflux for 72 hunder nitrogen. The mixture was diluted with water and extracted withethyl acetate. The organic extracts were combined, dried (MgSO₄) andevaporated in vacuo. The residue was purified on a silica SPE cartridgeeluting with ethyl acetate-cyclohexane mixtures to give the titlecompound (36 mg). LCMS RT=2.76 min

iii)3-{3-[(7-{[(2R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}heptyl)oxy]propyl}benzenesulfonamideacetate

A solution of3-(3-{[7-(benzyl{(2R)-2-[8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl]-2-hydroxyethyl}amino)heptyl]oxy}propyl)benzenesulfonamide(36 mg) in ethanol (10 ml) with ethyl acetate (2 ml) and glacial aceticacid (1 ml) was hydrogenated using 10% palladium on carbon (50% water byweight, 10 mg) and 20% palladium hydroxide on carbon (10 mg) for 19 h.The catalyst was removed by filtration and the filtrate was evaporatedin vacuo. The residue was purified on an aminopropyl SPE cartridge (2g), eluting with methanol-dichloromethane mixtures. Evaporation of theappropriate fractions with glacial acetic acid gave the title compound(15 mg). LCMS RT=2.26 min ES+ve m/z 532 (MH)⁺

Biological Activity

The potencies of the aforementioned compounds were determined using frogmelanophores transfected with the human beta 2 adrenoreceptor. The cellswere incubated with melatonin to induce pigment aggregation. Pigmentdispersal was induced by compounds acting on the human beta 2adrenoreceptor. The beta 2 agonist activity of test compounds wasassessed by their ability to induce a change in light transmittanceacross a melanophore monolayer (a consequence of pigment dispersal). Atthe human beta 2 adrenoreceptor, compounds of examples 1-13 had IC₅₀values below 1 μM.

Potency at other beta adrenoreceptor subtypes was determined usingchinese hamster ovary cells transfected with either the human beta 1adrenoreceptor or the human beta 3 adrenoreceptor. Agonist activity wasassessed by measuring changes in intracellular cyclic AMP.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1. A compound of formula (I)

or a salt, or solvate thereof, wherein: n is an integer of from 2 to 8;m is an integer of from 3 to 11, with the proviso that the sum of n+m isfrom 5 to 19; R¹ is hydrogen or —XSO₂NR⁶R⁷; wherein X is —(CH₂)_(p)— orC₂₋₆ alkenylene; p is an integer from 0 to 6; R⁶ and R⁷ areindependently selected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,CONR⁸R⁹, phenyl and phenyl(C₁₋₄alkyl)-, or R⁶ and R⁷, together with thenitrogen atom to which they are bonded, form a 5-, 6- or 7-memberednitrogen—containing ring; and R⁶ and R⁷ are each independentlyoptionally substituted by 1 or 2 groups independently selected fromhalo, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy-substituted C₁₋₆alkoxy,C₁₋₆haloalkyl, CO₂R⁸, SO₂R⁸R⁹, —CONR⁸R⁹, —NR⁸C(O)R⁹ or a 5-, 6- or7-membered heterocyclic ring; R⁸ and R⁹ are independently selected fromhydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, phenyl and phenyl(C₁₋₆alkyl)-; R²and R³ are independently selected from hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy,halo, phenyl and C₁₋₆haloalkyl; R⁴ and R⁵ are independently selectedfrom hydrogen and C₁₋₄ alkyl with the proviso that the total number ofcarbon atoms in R⁴ and R⁵ is not more than 4, and Ar is a group selectedfrom the group consisting of:

wherein R¹¹ represents hydrogen, halogen, —(CH₂)_(q)OR¹⁴, —NR¹⁴C(O)R¹⁵,—NR¹⁴SO₂R¹⁵, —SO₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —OC(O)R¹⁶ or OC(O)NR¹⁴R¹⁵, and R¹⁰represents hydrogen, halogen or C₁₋₄ alkyl; or R¹¹ represents —NHR¹⁷ andR¹⁰ and —NHR¹⁷ together form a 5- or 6-membered heterocyclic ring; R¹²represents hydrogen, halogen, —OR¹⁴ or —NR¹⁴R¹⁵; —OC(O)R¹⁶ or—OC(O)NR¹⁴R¹⁵; R¹³ represents hydrogen, halogen, haloC₁₋₄ alkyl, —OR¹⁴or —NR¹⁴R¹⁵; R¹⁴ and R¹⁵ each independently represents hydrogen or C₁₋₄alkyl, or in the groups —NR¹⁴R¹⁵, —SO₂NR¹⁴R¹⁵ and —OC(O)NR¹⁴R¹⁵, R¹⁴ andR¹⁵ independently represent hydrogen or C₁₋₄ alkyl or together with thenitrogen atom to which they are attached form a 5-, 6- or 7-memberednitrogen-containing ring, R¹⁶ represents an aryl (eg phenyl or naphthyl)group which may be unsubstituted or substituted by one or moresubstituents selected from halogen, C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy orhalo C₁₋₄ alkyl; and q is zero or an integer from 1 to 4; provided thatwhen R¹ is hydrogen Ar is not a group (a) wherein; R¹¹ is—(CH₂)_(q)OR¹⁴, q is zero or 1 and R¹² is OR¹⁴, or R¹¹ is—(CH₂)_(q)OR¹⁴, q is zero and R¹³ is OR¹⁴, or R¹¹ is —NR¹⁴SO₂R¹⁵ orNR¹⁴COR¹⁵ and R¹² is OR¹⁴, or R¹¹ and R¹³ both represent halogen and R¹²is NR¹⁴R¹⁵; Ar is not a group (b) wherein R¹¹ is —(CH₂)_(q)OR¹⁴ and R¹²is OR¹⁴; Ar is not a group (c), and when R¹ is XSO₂NR⁶R⁷, Ar is not agroup (a) wherein R¹¹ is (CH₂)_(q)OR¹⁴ or NR¹⁴COR¹⁵, and R¹² is OR¹⁴. 2.A compound of formula (I) according to claim 1 wherein, in the group Ar,R¹¹ represents halogen, —(CH₂)_(q)OR¹⁴, —NR¹⁴C(O)R¹⁵, —NR¹⁴SO₂R¹⁵,—SO₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —OC(O)R¹⁶ or OC(O)NR¹⁴R¹⁵, and R¹⁰ representshydrogen, or R¹¹ represents —NHR¹⁷ and R¹⁰ and —NHR¹⁷ together form a 5-or 6-membered heterocyclic ring; and R¹³ represents hydrogen, halogen,halo, C₁₋₄ alkyl, —OR¹⁴, or —NR¹⁴R¹⁵.
 3. A compound of formula (I)according to claim 1 wherein the group R¹ is attached to themeta-position relative to the —O—(CH₂)_(m) link.
 4. A compound offormula (I) according to claim 1 wherein R¹ represents SO₂NR⁶R⁷ whereinR⁶ and R⁷ are independently selected from hydrogen and C₁₋₆alkyl.
 5. Acompound of formula (I) according to claim 1 wherein R⁴ and R⁵ areindependently selected from hydrogen and methyl.
 6. A compound offormula (I) according to claim 1 wherein R² and R³ each representhydrogen.
 7. A compound of formula (I) according to claim 1 wherein n is5 or 6 and m is 3 or 4 such that m+n is 8, 9 or
 10. 8. A compound offormula (I) according to claim 1 wherein Ar represents a group selectedfrom the group consisting of:


9. A compound of formula (I) according to claim 8 wherein R¹ is hydrogenand Ar is selected from the group consisting of (ii), (v), (vi), (viii),(ix), (xi), (xii), (xiii), (xiv), (xv), (xvi), (xvii) and (xviii).
 10. Acompound of formula (I) according to claim 8 wherein R¹ is XSO₂NR⁶R⁷ andAr is selected from the group consisting of (iii), (iv), (xiv), (xv),(xvi) and (xix).
 11. A compound selected from the group consisting of:8-Hydroxy-5-((1R)-1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)quinolin-2(1H)-one;3-{4-[(6-{[(2R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;5-Hydroxy-8-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-2H-1,4-benzoxazin-3(4H)-one;3-{4-[(6-{[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;4-Hydroxy-7-((1R)-1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-1,3-benzothiazol-2(3H)-one;4-Hydroxy-7-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-1,3-benzothiazol-2(3H)-one;3-{4-[(6-{[(2R)-2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;3-(4-{[6-({2-Hydroxy-2-[5-hydroxy-6-(hydroxymethyl)pyridin-2-yl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;3-[4-({6-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]hexyl}oxy)butyl]benzenesulfonamide;3-{3-[(7-{[(2R)-2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]amino}heptyl)oxy]propyl}benzenesulfonamide;3-(3-{[7-({2-Hydroxy-2-[5-hydroxy-6-(hydroxymethyl)pyridin-2-yl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide;3-[3-({7-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]heptyl}oxy)propyl]benzenesulfonamide;3-{3-[(7-{[(2R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}heptyl)oxy]propyl}benzenesulfonamide;3-(3-{[7-({(2R)-2-[3-(Formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)heptyl]oxy}propyl)benzenesulfonamide;a salt thereof, and a solvate thereof.
 12. A method for the prophylaxisor treatment of a clinical condition in a mammal for which a selectiveβ₂-adrenoreceptor agonist is indicated, which comprises administering atherapeutically effective amount of a compound of formula (I) accordingto claim 1, or a pharmaceutically acceptable salt, or solvate thereof.13. (canceled)
 14. A pharmaceutical formulation comprising a compound offormula (I), according to claim 1, or a pharmaceutically acceptablesalt, or solvate thereof, and a pharmaceutically acceptable carrier orexcipient, and optionally one or more other therapeutic ingredients. 15.(canceled)
 16. A process for the preparation of a compound of formula(I), according to claim 1, or a salt, or solvate thereof, whichcomprises: deprotecting a protected intermediate of formula (II):

or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, m and n are asdefined for the compounds of formula (I) R²⁵ represents an optionallyprotected form of Ar, and R²⁶ and R²⁷ each independently representeither hydrogen or a protecting group, provided that the compound offormula (II) contains at least one protecting group

wherein said process may further optionally comprise one or more of thefollowing steps in any order: (i) removing any protecting groups; (ii)separating an enantiomer from a mixture of enantiomers; (iii) convertingthe product to a corresponding salt, solvate, or (iv) converting a groupR¹, R² and/or R³ to another group R¹, R² and/or R³.
 17. A compound ofthe formula (I) according to claim 1, wherein m is an integer rangingfrom 3 to
 7. 18. A compound of the formula (I) according to claim 1,wherein the sum of n+m ranges from 5 to
 12. 19. A compound of theformula (I) according to claim 1, wherein p is an integer ranging from 0to
 4. 20. A method according to claim 12, wherein the mammal is a human.21. A method according to claim 12, wherein the clinical condition isasthma.
 22. A method according to claim 12, wherein the clinicalcondition is COPD.
 23. A process for the preparation of a compound offormula (I), according to claim 1 or a salt, or solvate thereof, whichcomprises: reacting a compound of formula (XIII):

Wherein Ar is as defined above with a compound of formula (VI):

wherein L is a leaving group and R¹, R², R³, R⁴, R⁵, n and m are asdefined for compounds of formula (I); wherein said process may furtheroptionally comprise one or more of following steps in any order: (i)removing any protecting groups; (ii) separating an enantiomer from amixture of enantiomers; (iii) converting the product to a correspondingsalt, solvate, or (iv) converting a group R¹, R² and/or R³ to anothergroup R¹, R² and/or R³.
 24. A process according to claim 23, wherein theleaving group comprises a halo group.
 25. A process according to claim24, wherein the halo group is selected from the group consisting ofchloro, bromo, and iodo.
 26. A process according to claim 23, whereinthe leaving group comprises a sulphonate group.
 27. A process accordingto claim 26, wherein the sulphonate group is a methanesulphonate group.28. A process for the preparation of a compound of formula (I),according to claim 1, or a salt or solvate thereof, which comprises:reacting a compound of formula (XV):

wherein L is a leaving group, with an amine of formula (XVI):

wherein R¹, R², R³, R⁴, R⁵, n and m are as defined for formula (I); andwherein said process may further optionally comprise one or more of thefollowing steps in any order: (i) removing any protecting groups; (ii)separating an enantiomer from a mixture of enantiomers; (iii) convertingthe product to a corresponding salt, solvate, or (iv) converting a groupR¹, R² and/or R³ to another group R¹, R² and/or R³.
 29. A processaccording to claim 28, wherein the leaving group comprises a halo group.30. A process according to claim 28, wherein the halo group is selectedfrom the group consisting of chloro, bromo, and iodo.
 31. A processaccording to claim 28, wherein the leaving group comprises a sulphonategroup.
 32. A process according to claim 28, wherein the sulphonate groupis a methanesulphonate group.
 33. A process for the preparation of acompound of formula (I), according to claim 1 or a salt or solvatethereof, wherein said process is selected from the group consisting of(i) and (ii): (i) reacting a compound of formula (XIII):

Wherein Ar is as hereinbefore defined and R³⁴ is a chiral auxiliarygroup, with a compound of formula (XVII):

wherein R¹, R², R³, R⁴, n and m are as hereinbefore defined; optionallyfollowed by removing said chiral auxiliary group R³⁴; and (ii) reactinga compound of formula (XVIII):

wherein Ar is as hereinbefore defined; with an amine of formula (XVI):

as hereinbefore defined, under conditions suitable to effect reductiveamination, wherein said process may further optionally comprise one ormore of the following steps in any order: (i) removing any protectinggroups; (ii) separating an enantiomer from a mixture of enantiomers;(iii) converting the product to a corresponding salt, solvate, (iv)converting a group R¹, R² and/or R³ to another group R¹, R² and/or R³.